The genetics of the H-Y antigen system and its role in sex determination.

Abstract

THE GENETICS OF THE H-Y ANTIGEN SYSTEM AND ITS ROLE IN SEX DETERMINATION JEANNE MONROY MECK* I. Introduction to H-Y Antigen A. H-Y antigen and sex determination According to the central dogma of sexual development, mammals have an inherent tendency to differentiate as females. This theory, proposed by Alfred Jost (1947-1952), stemmed from the finding that castrated mammalian embryos develop as females. At that time chromosomal sex was believed to be solely responsible for the development of ovaries (XX) or testes (XY). If the Y chromosome were present, the individual would develop as a male; if the Y chromosome were absent, it would develop as a female [I]. At present it is believed that it is not the Y chromosome itself, but one or more genes coding for a molecule known as the "H-Y antigen," which determines maleness in mammals [2]. The H-Y antigen is present on the surface of all nucleated cells in normal male mammals and is synthesized as early as the eight-cell stage in embryogenesis [3]. Presence of the H-Y antigen on cells of the indifferent gonads of male embryos appears to act as a signal for the initiation of testis formation. Once formed, the embryonic testes secrete the male hormone testosterone which causes differentiation of the Wolffian ducts to form the male sex accessories: the epididymis, vas deferens, and seminal vesicles. External male genitalia develop as a result of the conversion of testosterone to dihydrotestosterone. Dihydrotestosterone is a potent androgen and is considered to be the active form of testosterone. "Anti-Mullerian hormone" is also secreted by the testes and is responsiThe author is very grateful to Drs. Benson Ginsburg, Paul Tocci, and Herbert Lubs for their constructive criticism and encouragement in the preparation ofthis manuscript. This work was supported by the Hayward Foundation. *Mailman Center for Child Development, University of Miami School of Medicine, Miami, Florida 33101.© 1984 by The University of Chicago. All rights reserved. 0031-5982/84/2704-0391$01.00 560 I JeanneMonroy Meek ¦ Genetics ofthe H-YAntigen System ble for the regression of the Mullerian ducts that would otherwise develop into fallopian tubes, uterus, and part of the vagina [4]. In the absence of H-Y antigen on cells of the embryonic indifferent gonad, testes do not develop, the Wolffian ducts degenerate, and the Mullerian ducts develop instead, resulting in a female phenotype [5]. B.discovery of the H-Y antigen The existence of the H-Y antigen was first discovered by Eichwald and Silmser in 1955 [6]. They found that male-to-female skin grafts were rejected in two inbred strains of mice, whereas female-to-male, male-tomale , and female-to-female grafts almost always took. That an immunological phenomenon was at work was shown by (1) the occurrence of second-set reactions (i.e., those females which rejected male skin grafts rejected subsequent grafts more quickly) and (2) induction of tolerance in adult females by exposure as neonates to male cells. Furthermore , it was suggested that Eichwald and Silmser's findings were caused by an antigen coded for by a short segment ofthe Y chromosome which does not pair with the X chromosome, thus keeping.it male specific . Some findings which implicated the Y chromosome included: (1) cultured testicular teratomas containing cells with a Y chromosome were H-Y antigen positive, but when the Y chromosome was lost in passage so was the H-Y antigen [7], and (2) XYY males were found to have approximately twice as much H-Y as XY males [8]. Antigens involved in tissue transplantation, such as skin grafting, are called "histocompatibility" antigens. The name "H-Y" for this particular antigen stems from the fact that it is a histocompatibility antigen involving the Y chromosome [9]. C.H-Y antigen and phylogeny The H-Y antigen shows extreme evolutionary conservation through hundreds of millions of years of evolution. Murine H-Y antigen has been found to be cross-reactive with a wide variety of animals, including humans [10], rats, rabbits [11], dogs [12], mole voles [13], birds, frogs [11], and even invertebrates such as the lobster, beetle, cockroach [14], and teleost fish [15]. However, the...